Is SEC63 p.His669fs (c.2006_2007del) pathogenic?

SEC63 p.His669fs (c.20062007del) is classified Pathogenic/Likely pathogenic in SEC63 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-04-04). Very rare (popmax 0.00227%, eas); Associated with SEC63-related disorder.

What condition is associated with SEC63 p.His669fs (c.2006_2007del)?

SEC63 p.His669fs (c.2006_2007del) is associated with SEC63-related disorder, autosomal dominant polycystic liver disease, polycystic liver disease 2 (ClinVar).

How common is SEC63 p.His669fs (c.2006_2007del) in the general population?

SEC63 p.His669fs (c.2006_2007del) is very rare (popmax 0.00227%, eas) (gnomAD).

SEC63 p.His669fs

c.2006_2007del · rs1403483213 · VCV1255624

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00227%, eas)

Conditions

SEC63-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 19 of 21
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00227% East Asian · 1/44,116 alleles

Filtering AF 0.000184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000503% 8/1,591,672 alleles · very rare exomes 5/1,447,070 · genomes 3/144,602 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00227%	44,116
South Asian	0.00111%	90,460
European (non-Finnish)	0.000513%	194,996

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SEC63
Protein: p.His669fs
Coding: c.2006_2007del
MANE Select: NM_007214
dbSNP: rs1403483213
Type: Deletion
Location: chr6:107876591 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 669: the sec63 2 domain; a UniProt-annotated variant site (in pcld2)

Full SEC63 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

SEC63-related disorder

Also linked: autosomal dominant polycystic liver disease polycystic liver disease 2

Similar variants

SEC63 c.125-13del Likely benign ★★ same condition
SEC63 c.1936-11_1936-9del Benign/Likely benign ★★ same condition
SEC63 c.1936-9del Benign/Likely benign ★★ same condition
SEC63 c.340-12_340-11del Benign/Likely benign ★★ same condition
SEC63 c.340-12_340-8del Benign/Likely benign ★★ same condition
SEC63 c.340-9_340-7del Benign/Likely benign ★★ same condition
SEC63 c.506_514+3del Likely pathogenic ★ same condition
SEC63 p.Lys402fs Likely pathogenic ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/sec63-p-his669fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown